Cancer immunotherapy is racking up more successes

Print 23 March 2015
Anette Breindl / BioWorld

Immunotherapy can deliver remissions that last long enough to make the most hardened oncologist consider the possibility that their patient might be cured. But only a minority of patients responds to immunotherapy at all.

As a result, the key challenge with immunotherapies is not how to make their effects last. It is how to get patients to react to them in the first place.

A paper recently published Nature showed progress on that front in one of the toughest indications there is. In a clinical trial with 12 patients, scientists at Duke University were able to significantly prolong the lives of subjects with glioblastoma multiforme by treating them with a dendritic cell vaccine and what was essentially an adjuvant, a preconditioning tetanus shot that induced inflammation at the vaccination site.

Median overall survival of those who received only the vaccine was 18.5 months, which was "consistent with" the survival of patients receiving the standard of care, the authors wrote.

Of the six patients who received the preconditioning shot, three were still alive at the end of the study, three years after treatment had started. And one of those three is still alive today, almost nine years after her doctors told her she most likely had only months to live.

Many a treatment that looks promising in the first dozen patients can look considerably less so under the harsh glare of pivotal trial statistics, of course. But "in the deadliest diseases, even small numbers really mean something," Reiner Laus told BioWorld Insight.

VIRTUAL COMPANY

Laus is the president and CEO of Annias Immunotherapeutics Inc., a so-far virtual start-up that has licensed the technology behind the trial results from Duke University, where it was developed and where the trial was conducted. Annias is currently raising funding for larger trials, both of the dendritic cell vaccine described inNature and for an off-the shelf peptide vaccine that targets the same antigen.

Laus said that although the preconditioning aspect of the work has received a lot of attention, the choice of antigen is also noteworthy. That antigen is pp65, and although it is expressed specifically on tumor cells, it is a viral protein, from cytomegalovirus (CMV).

While the immune system can be ambivalent about many tumor targets – and for good reason, given that they are still human proteins, if mutated ones – viral proteins, Laus noted, are "something the immune system loves to attack, and is very good at attacking, too."

Another advantage of targeting pp65 is that it is expressed in many cancers, including breast, prostate and colorectal cancers, which account for the largest number of cancer cases overall. CMV is a herpesvirus, and the majority of the U.S. population has a chronic CMV infection from childhood onward. That infection is usually of no consequence, as there are large numbers of T cells suppressing it. But in the immunocompromised environment of a tumor, CMV can be reactivated – and, incidentally, present a tumor-specific antigen, since the virus is still suppressed in healthy cells.

Laus is convinced that cancer vaccines ultimately will become a major pillar of cancer immunotherapy. Whether dendritic cell vaccines will be a key component of that is more difficult to predict. He was part of the team that developed Provenge (sipuleucel-T). (See BioWorld Today, April 29, 2010, and Nov. 11, 2014.)

"Everything needs a precedent," Laus said. "For cell-based active immunotherapies, that hasn't really happened yet . . . Provenge was approved, but it wasn't commercially successful."

CLINICAL SUCCESSES

The therapeutic approach that has racked up the clinical successes in cancer immunotherapy to date – antibodies – has "a history that is not unlike that of cancer vaccines," he noted. Initial excitement was followed by setbacks, a period in which antibody therapies were considered "useless," and then, with the success of Rituxan (rituximab, Biogen Idec Inc. and Roche AG), biopharma love has turned them into a major therapeutic modality.

The technology that is currently viewed as most promising by the investment community to set such a precedent for cell-based cancer immunotherapy, he added, it is CAR T cells, which have seen spectacular remissions in early phase trials. (See BioWorld Today, April 14, 2013.)

Laus said he thinks their ability to bring patients back from the brink of death may be sufficient to keep researchers slogging through the inevitable setbacks and keep investors excited about cell-based therapies, despite their challenges. "If the data are good enough, it doesn't really matter what the modality is."

So far, the clinical successes in cancer immunotherapies have been antibodies, and they have been checkpoint inhibitors. Opdivo (nivolumab, Bristol Myers Squibb Co), Keytruda (pembrolizumab, Merck & Co. Inc.) and Yervoy (ipilimumab, Bristol Myers Squibb Co.) override the immune system inhibition of T-cell checkpoints that are meant to prevent immune system hyperactivation. Opdivo and Keytruda target the PD-1/PD-L1 interaction, while Yervoy blocks another checkpoint inhibitor, CTLA4.

Another paper, published online in Nature, showed that inhibitors of both checkpoints synergized with each other, as well as with radiation, in advanced melanoma. That work suggests that combination treatment of immunotherapies with each other, as well as with targeted therapies, would improve the response rate.

There are many more checkpoint inhibitors than PD-1/PD-L1, and Ali Fattaey, the president and CEO ofCuris Inc., said he thinks there will ultimately be test panels that look at how given tumors evade the immune system, much like current gene tests look at their mutational landscapes.

"Tumors turn off T cells – that is one of their hallmarks," Fattaey told BioWorld Insight. "And much like for every other hallmark of cancer, they must have multiple different ways of doing so. . . . I don't think that every cancer is going to fit through the PD-1 window."

Curis is in a partnership with Aurigene Discovery Technologies Ltd. to develop small-molecule checkpoint inhibitors. If combination treatments for checkpoint inhibition become a clinical strategy, small molecules will allow more precise timing as well as being a financially preferable option to combining antibodies, which are expensive enough one at a time.

Though a PD-1 inhibitor is furthest along, the companies also are working on other checkpoints. And ultimately, he said, immunotherapies will broaden still further. "In the tumor microenvironment, there are many other cells besides T cells," Fattaey said.

Dendritic cells, for example.

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